5-Adamantane-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acid amide is one of compounds having an adamantine group as a substituent, and is presented as an active ingredient of a cosmetic composition because it has an excellent whitening effect by inhibiting melanin existing in the outer layer of the human skin.
Regarding to preparation of the above compound, in Korean Patent Publication No. 2013-0015954, the compound is prepared according to the following Reaction Formula.

Specifically, 5-adamantane-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acid amide is prepared through the steps of: (i) reacting 2,4-dihydroxy benzoic acid and 1-adamantanol in dichloromethane as a solvent at room temperature in the presence of acetic acid and sulfuric acid as a catalyst to synthesize 5-adamantanyl-2,4-dihydroxy benzoic acid; (ii) reacting the 5-adamantanyl-2,4-dihydroxy benzoic acid and dimethyl sulfate in the presence of sodium hydroxide or potassium hydroxide to synthesize 5-adamantanyl-2,4-dimethoxy benzoic acid; and (iii) reacting the 5-adamantanyl-2,4-dimethoxy benzoic acid with benzyl amine in the presence of N-hydroxy succinimide and N,N′-dicyclohexyl carbodiimide.
In this preparing method, when the acetic acid and the solvent used for preparing the 5-adamantanyl-2,4-dihydroxy benzoic acid of the step (i) are consumed 8 times or more and 2 times or more, respectively, compared to the reactant, the reaction time is required at least 5 hours, and a yield is about 80 to 85%.
Further, in the step (iii), a coupling agent for coupling, for example, N-hydroxy succinimide/1,3-dicyclohexyl carbodiimide (HOSu/DCC), SOCl2 or 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC) in dichloromethane, cyanuric chloride in MeCN, B(OH)3 in toluene and the like, is used under expensive water/dioxane solvent, and accordingly, the solvent is limitedly required. The yield of the compound thus obtained is very low as about 30%, and the purity is also low due to a complex mixture remained in the final product.
In particular, dihydroxy benzyl amine to be used as a reactant in the step (iii) is prepared through the following steps.

In the above reaction, dihydroxy benzaldehyde as a starting material is reacted with sodium carbonate in methanol or ethanol for 5 hours for activation, and then hydrochloric acid in methanol or ethanol is added thereto for additional reaction to prepare an oxime compound.
Then, reduction reaction is performed by using high-pressure hydrogen gas in the presence of a catalyst, in which Pd is loaded in a carbon support, to prepare dihydroxy benzyl amine. At this time, the reaction takes a long time about 5 hours, nevertheless it show a yield of about 50%. Moreover, this reaction has problems that it should use expensive Pd, and the process is complicated and process cost is increased because hydrogen gas of 50 psi is used during the reaction.
Also, as process increases in size, there were many problems unsuitable for mass production, for example, a yield decreases, irregular production pattern is form or separation of a mixture becomes impossible.
Thus, there are many restrictions on industrial application of the benzoic acid amide compound in spite of it excellent effect related to whitening. Therefore, it is needed to develop a novel preparation method with improved production efficiency.